Leishmania donovani, a prototypic intracellular pathogen of man, is an important cause of morbidity and mortality throughout the developing world. It is inoculated as an extracellular, flagellated promastigote by the sandfly, its insect vector. In mammals, it flourishes solely within mononuclear phagocytes as an amastigote. A systematic study of host defense mechanisms during sequential stages of infection is proposed in order to advance our understanding of the biology of this intracellular protozoan and to facilitate development of an effective approach toward immunoprophylaxis. An in vivo model has been developed to determine how promastigotes escape killing by PMN and lysis by serum complement. Non-immune and immune hamsters made granulocytopenic with nitrogen mustard are used. The role of anti-Leishmanial antibody in enhancing complement mediated lysis and ingestion by PMN will be studied to determine if antibody provides protection against infection. The importance of antibody-induced promastigote surface antigen modulation in parasite escape from the deleterious effects of complement and PMN will be determined in vitro. Macrophages are the sole sanctuary for L. donovani in man. Promastigotes attach to human monocyte-derived macrophages, are ingested, convert to the amastigote state and multiply. In vitro studies are proposed to identify a way to block attachment, facilitate intracellular killing of promastigotes, prevent conversion of promastigotes to the more resistant amastigote state, and inhibit intracellular multiplication. The mechanism by which L. donovani is killed in the immune host and the manner by which the parasite suppresses cell-mediated immune mechanisms during infection will be studied in order to find a way to enhance immune mechanisms against it. The effect of antigen and mitogen stimulated lymphokines one the oxidative response during phagocytosis and on intracellular parasite survival will be determined. The role of antibody-dependent and antibody-independent monomuclear cell cytotoxicity will be assessed. Studies will be done to determine if parasite, infected macrophage, or serum factors inhibit lymphocyte blastogenesis and if there is a suppressor T-cell population. Completion of this study will greatly enhance understanding of the immune response to L. donovani in specific and to intracellular parasites in general.